tbuckley/cabot-search huggingface dataset:
Abstract 5045: Genomics and pathology based deep learning to predict cancers of unknown primary
Authors: Yanan Wang, Guanjun Zhang, Xi Liu, Yanfeng Xi, Pan Wang, Yuman Zhang, Xing Li
Journal: Cancer Research (2022)

Abstract Background: Cancers of unknown primary (CUP) are a type of metastatic cancer. However, their primary anatomical site of origin cannot be clinically determined using routine history inquiries, laboratory tests, endoscopy, and imaging. CUP account for ~3-5% of cancers. Empirical chemotherapy (paclitaxel, carboplatin, etc.) is generally used, although the curative effect is poor. Finding the primary site of origin for CUP patients is of great significance for clinical treatment. Method: Our study employed 10,001 pathological images and 9,775 gene detection data points based on whole-exome sequencing (WES) or YUANSU®(OrigiMed, Shanghai, China) for primary cancer within a database containing 32 common cancers. We applied machine learning algorithms (autoML, Transformers, attention) and constructed two diagnostic models. The models diagnosed by identifying pathological images (Model 1) and genomic data (Model 2). Accuracy for the two models was verified. Result: Both models were evaluated using top-k differential diagnosis accuracy, in other words how often the ground truth label was found for k highest confidence predictions for the model. The pathological model (Model 1) achieved a top-3 accuracy of 83.38% and a top-5 accuracy of 90.36%. Using the same methodology, genomic model (Model 2) results were 87.5% and 92.2%, respectively. Conclusion: Using deep learning, we developed diagnostic models for CUP based on pathological images and genomic data. Accuracy for both the pathological image model (Model 1) and the genomic data model (Model 2) was not satisfactory. To improve diagnostic accuracy, further studies on developing a diagnostic model that combines pathological imaging and genomic data are ongoing.. Citation Format: Yanan Wang, Guanjun Zhang, Xi Liu, Yanfeng Xi, Pan Wang, Yuman Zhang, Xing Li. Genomics and pathology based deep learning to predict cancers of unknown primary [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5045.
Abstract 2505: Predicting prognosis in PFA ependymoma and group 3/4 medulloblastoma methylomes using interpretable epigenetic models
Authors: Indy Ng, Alexander Fricke, Shraddha Pai
Journal: Cancer Research (2022)

Abstract Introduction: Our goal is to develop interpretable, prognostic models for Group 3/4 medulloblastoma (G3/4 MB) and PFA ependymomas (PFA-EP) using brain tumor DNA methylomes. Our models use prior knowledge of genome regulation and may identify cellular processes that help develop molecular therapies. We previously developed a classifier algorithm, netDx, which uses similarity networks to integrate heterogeneous patient data and predict outcome1. netDx demonstrates excellent performance and allows measures to be grouped into biologically meaningful features (e.g. grouping genes into pathway features). Ependymoma Methods: We predicted survival in PFA-EP using 569 methylomes2 (Illumina 450K). Using netDx, we evaluated a model that grouped CpG-level methylation into sets reflecting 25 cell types from the developing human cerebellum, 3 chromatin states, EZH2 binding sites, and brain super enhancers (80:20 train/test split, feature selection &amp;gt;=8/10; 10 splits). This model was compared to a baseline lacking prior knowledge. Preliminary Results: Organizing methylomes by prior knowledge significantly improves prognostic prediction (Table 1, p &amp;lt; 5x10-3, one-sided WMW). Features that predict prognosis are consistent with known dysregulation in PFA-EP2 (Table 1). G3/4 MB Methods: We predicted binarized survival using 285 methylomes3 (Illumina 450K), using identical methods as above. Preliminary results: Tumor methylomes carry predictive signal for survival prediction (Table 1), consistent with previous findings. We are currently evaluating the effect of including prior knowledge. Interim Conclusion: Prior knowledge can improve survival prediction in PFA-EP and identifies features reflecting tumor biology. We are interested in extending interpretable modeling to other tumours.1. Pai et al. (2019) Mol Sys Biol. 15. 2. Pajtler et al. (2018) Acta Neuropathol. 136. 3. Northcott et al. (2017) Nature 547. Table 1. Average model performance and top features. Dataset Predictor design AUPR (mean+/- SD, 10 train/test splits) Predictive features PFA-EP; 252 good/317 poor survivors2 DNAm, no prior knowledge 64.2 +/- 2.3 n/a * Covariates: CXOrf67 mutation status, sex DNAm, prior knowledge* 67.5 +/- 3.5(p &amp;lt; 5x10-3; one-sided WMW test compared to baseline model) CXOrf67mut, methylation in: {H3K9me3 sites; marker genes for ependymal cells of choroid plexus; marker genes for multiple interneuron classes} G3/4 MB: 146 good/139 poor survivors3 DNAm, no prior knowledge 0.61 +/- 6.3 n/a ** Covariates: age, sex DNAm, prior knowledge** In progress Citation Format: Indy Ng, Alexander Fricke, Shraddha Pai. Predicting prognosis in PFA ependymoma and group 3/4 medulloblastoma methylomes using interpretable epigenetic models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2505.
Abstract 1266: Circulating immune biomarkers in peripheral blood reflect the effect of a CD200 immune checkpoint targeted immunotherapy in pet dogs with high-grade glioma
Authors: Francisco W. Puerta Martinez, Sathya Schnell, Susan Arnold, Elizabeth G. Pluhar, Michael Olin
Journal: Cancer Research (2022)

Abstract The extent to which immune cell phenotypes in the peripheral blood reflect intratumoral immune activity prior to and early in cancer immunotherapy is unclear. Here we studied the population dynamics of immune cells and immune phenotypic changes, using clinical blood samples and a multicolor flow cytometry analysis. These samples were serially obtained from a cohort of high-grade glioma canine patients enrolled in a trial with an immunotherapy that targets the CD200/CD200R immunological synapse. This therapy consists of an alternative checkpoint inhibitor peptide (CD200AR-L) that modulates the CD200 immune checkpoint, currently being used in an adult phase I safety trial for recurrent glioblastoma trial (NCT04642937) and a canine high-grade spontaneous glioma trial (U01CA224160-01). We found evidence of a strong effect of the therapy on peripheral immune cells in responder versus nonresponder dogs. Upon initiation of therapy, immune effector cell proliferation increased in responsive patients, whereas in nonresponders immune cell populations either didn’t change significantly or an increase in immunosuppressive phenotypes was observed. Cell populations such as MDSC, regulatory T cells and exhausted T cells were predominantly higher in nonresponder dogs. These data showed that peripheral immune cell phenotypes were linked to the outcome of the immunotherapy, thus dogs with better immune cell profiles, including increased cytotoxic differentiation, had a better prognosis and longer overall survival rates. Taken together, these results suggest that variation in patient responsiveness can be explained by differences in peripheral immune cell proliferation and differentiation soon after the initiation of immunotherapy. Citation Format: Francisco W. Puerta Martinez, Sathya Schnell, Susan Arnold, Elizabeth G. Pluhar, Michael Olin. Circulating immune biomarkers in peripheral blood reflect the effect of a CD200 immune checkpoint targeted immunotherapy in pet dogs with high-grade glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1266.
Abstract 1130: CETSA interaction proteomics define specific RNA modification pathways as key components of fluorouracil based cancer drug cytotoxicity
Authors: Smaranda Bacanu, Ying Yu Liang, Anderson D. Ramos, Nayana Prabhu, Pär Nordlund
Journal: Cancer Research (2022)

Abstract Introduction: Our current understanding of the mechanism of action (MoA) of many cancer drugs is still incomplete. This hampers efforts in establishing efficient personalised medicine regimens, the optimisation of combination therapies, and the development of next generation drugs. Results: Here, we apply a high-resolution implementation of the proteome-wide cellular thermal shift assay (CETSA) to follow protein interaction changes induced by the antimetabolite 5-fluorouracil (5-FU) and related nucleosides. We focus on the relatively early drug effects, up to 12 hours, when this time frame is less accessible to other omics methods, while critical for defining drug MoAs. We confirm anticipated effects on the known main target, thymidylate synthase (TYMS), and enzymes in pyrimidine metabolism and DNA damage pathways. However, most interaction changes we see are for proteins previously not associated with the MoA of 5-FU, including wide-ranging effects on RNA modification and processing pathways. Attenuated responses of specific proteins in a resistant cell model identify key components of the 5-FU MoA, where intriguingly the abrogation of TYMS inhibition is not required for cell proliferation. Conclusions: When 5-FU is one of the most used and studied cancer drugs, this novel information significantly expands our understanding of the 5-FU MoA and will be important to direct further work towards dissecting its complete MoA. Furthermore, the CETSA responses of several proteins now provide ideal readouts for directly monitoring whether the required 5-FU effects are accomplished and can now be examined as CETSA-based candidate biomarkers in clinical studies. Together, this work also validates an efficient strategy for dissecting the MoA of cancer drugs, which could be broadly applicable to other cancer drugs in clinical use or in development. Citation Format: Smaranda Bacanu, Ying Yu Liang, Anderson D. Ramos, Nayana Prabhu, Pär Nordlund. CETSA interaction proteomics define specific RNA modification pathways as key components of fluorouracil based cancer drug cytotoxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1130.
Abstract 1591: Convergence of antigenic diversity and Tex-cell stability fatally constrains immune surveillance in non-small cell lung cancer (TRACERx) and HIV-1 infection (Protocol C)
Authors: James L. Reading, Rachel Rosenthal, Oriol Pich, Samuel Gamble, Seng Anakin Ung, Teerapon Sahwangarrom, Betty Gration, Yien Ning Sophia Wong, Lucas Black, Benny Chain, Jonathan Hare, Sergio A. Quezada, Charles Swanton
Journal: Cancer Research (2022)

Abstract T cells recognize cognate antigen and elicit effector function to eliminate target cells. In chronic infection and cancer, exhausted T cells with impaired effector function and narrow TCR repertoires must respond to vast and diverse antigenic landscapes, favoring immune escape. Here we test whether T cell exhaustion and antigenic diversity converge to drive fatal immune failure in chronic infection and cancer. We leveraged over 600 primary longitudinal samples from the Protocol C (IAVI) and TRACERx (CRUK) studies to track the natural course of HIV-1 infection and non-small cell lung cancer (NSCLC), respectively, using high parameter flow cytometry, genome sequencing and TCRseq, complemented with focused scRNAseq and antigen specific profiling. In both diseases systemic Tcf1-Tox+Eomes+PD1+ T (Tex) cells track antigen burden and predict adverse outcome, independent of host clinical status. In HIV-1 infection, Tex cells are clonally restricted and rapid Gag RNA sequence divergence accompanies higher viral loads and lower CD4 counts. Similarly, in lung cancer peripheral Tex cells harbor hyper-expanded TCRs, contract after resection and reconstitute at recurrence with strikingly preserved clonal hierarchies, creating a ‘specificity gap’ that could be exploited by subclonal evolution. Commensurate with this model, we discover that a high level of systemic Tex cells coupled with either elevated Gag diversity in HIV-1 infection, or higher mutational or copy number heterogeneity in lung cancer defines patients with the poorest clinical outcome. We propose a unifying model of immune failure in chronic infection and cancer where genomic diversity and T cell exhaustion co-ordinately diminish human immune protection. Citation Format: James L. Reading, Rachel Rosenthal, Oriol Pich, Samuel Gamble, Seng Anakin Ung, Teerapon Sahwangarrom, Betty Gration, Yien Ning Sophia Wong, Lucas Black, Benny Chain, Jonathan Hare, Sergio A. Quezada, Charles Swanton. Convergence of antigenic diversity and Tex-cell stability fatally constrains immune surveillance in non-small cell lung cancer (TRACERx) and HIV-1 infection (Protocol C) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1591.
Effects of Short-Term Potassium Chloride Supplementation in Patients with CKD
Authors: Martin Gritter, Rosa D. Wouda, Stanley M.H. Yeung, Michiel L.A. Wieërs, Frank Geurts, Maria A.J. de Ridder, Christian R.B. Ramakers, Liffert Vogt, Martin H. de Borst, Joris I. Rotmans, Ewout J. Hoorn
Journal: Journal of the American Society of Nephrology (2022)

Observational studies suggest that adequate dietary potassium intake (90-120 mmol/day) may be renoprotective, but the effects of increasing dietary potassium and the risk of hyperkalemia are unknown.This is a prespecified analysis of the run-in phase of a clinical trial in which 191 patients (age 68±11 years, 74% males, 86% European ancestry, eGFR 31±9 ml/min per 1.73 m2, 83% renin-angiotensin system inhibitors, 38% diabetes) were treated with 40 mmol potassium chloride (KCl) per day for 2 weeks.KCl supplementation significantly increased urinary potassium excretion (72±24 to 107±29 mmol/day), plasma potassium (4.3±0.5 to 4.7±0.6 mmol/L), and plasma aldosterone (281 [198-431] to 351 [241-494] ng/L), but had no significant effect on urinary sodium excretion, plasma renin, BP, eGFR, or albuminuria. Furthermore, KCl supplementation increased plasma chloride (104±3 to 105±4 mmol/L) and reduced plasma bicarbonate (24.5±3.4 to 23.7±3.5 mmol/L) and urine pH (all P<0.001), but did not change urinary ammonium excretion. In total, 21 participants (11%) developed hyperkalemia (plasma potassium 5.9±0.4 mmol/L). They were older and had higher baseline plasma potassium.In patients with CKD stage G3b-4, increasing dietary potassium intake to recommended levels with potassium chloride supplementation raises plasma potassium by 0.4 mmol/L. This may result in hyperkalemia in older patients or those with higher baseline plasma potassium. Longer-term studies should address whether cardiorenal protection outweighs the risk of hyperkalemia.Clinical trial number: NCT03253172.
SETDB1 Restrains Endogenous Retrovirus Expression and Antitumor Immunity during Radiotherapy
Authors: Dong Pan, Xuhui Bao, Mengjie Hu, Meng Jiao, Fang Li, Chuan-Yuan Li
Journal: Cancer Research (2022)

Abstract The type I interferon response plays a pivotal role in promoting antitumor immune activity in response to radiotherapy. The identification of approaches to boost the radiation-induced type I interferon response could help improve the efficacy of radiotherapy. Here we show that the histone methyltransferase SETDB1 is a potent suppressor of radiation-induced endogenous retrovirus expression. SETDB1 inhibition significantly enhanced the efficacy of radiotherapy by promoting radiation-induced viral mimicry to upregulate type I interferons. SETDB1 expression correlated with radiotherapy efficacy in human non–small cell carcinoma and melanoma patients. In a murine tumor model, genetic deletion of Setdb1 significantly enhanced radiotherapy efficacy, and Setdb1-deficient tumors had enhanced intratumoral lymphocyte infiltration, an observation confirmed in human cancer samples. Setdb1 deficiency led to increased basal and radiation-induced endogenous retrovirus (ERV) expression, enhanced MDA5/MAVS signaling, and upregulated type I interferons, which were essential for SETDB1 deficiency–induced radiosensitization. Taken together, these data suggest that inhibition of SETDB1 is a promising approach to enhance cancer radiotherapy efficacy by promoting radiation-induced viral mimicry and antitumor immunity through ERV induction. Significance: The identification of the SETDB1-mediated suppression of radiotherapy-induced viral mimicry reveals SETDB1 inhibition as a potential approach to sensitize tumors to radiotherapy by enhancing the type I interferon response.
Abstract 2514: Pancreatic cancer subtype-specific secreted factors determine the immunosuppressive tumor microenvironment
Authors: Stefanie Bärthel, Chiara Falcomatà, Sebastian A. Widholz, Albulena Toska, Fabio Boniolo, Constantin Schmitt, Vanessa Gölling, Jonathan Swietlik, Jonas Mir, Moritz Jesinghaus, Felix Meissner, Roland Rad, Marc Schmidt-Supprian, Dieter Saur
Journal: Cancer Research (2022)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a complex disease displaying genetic heterogeneity along with a tumor microenvironment (TME) unique in its composition. Whereas the PDAC TME is known to be highly immunosuppressive, it remains elusive how distinct genetic alterations affect TME cell type recruitment and how this, in turn, influences progression and treatment outcome. Therefore, we systematically investigated the TME composition and tumor-immune crosstalk in molecular PDAC subtypes. We delineated the TME landscape of a comprehensive tumor cohort derived from Kras-driven PDAC mouse models by integrating single cell RNA-sequencing (scRNA-seq) with histopathological analysis, tissue RNA-seq followed by deconvolution and flow cytometry immunophenotyping. Our results show that distinct molecular PDAC subtypes recruit divergent subpopulations of infiltrating immune cells, most notably evidenced by major differences in frequency and phenotype of macrophages and neutrophils. Functional secretome analysis of well-characterized Kras-driven mouse and primary human PDAC cell lines revealed subtype-specific factors which differ between the two main transcriptional subtypes of PDAC (classical and mesenchymal). Accordingly, crosstalk between tumor and immune cells inferred by interaction probability analysis through ligand-receptor pairs from scRNA-seq data nominates the CSF signaling network as a key player in mesenchymal PDAC, whereas CXCL signal hubs mediate higher infiltration of immunosuppressive neutrophils in classical tumors. Our findings contribute to the understanding of PDAC subtype-specific biology and aid the identification of potential immunotherapeutic vulnerabilities thereof. Citation Format: Stefanie Bärthel, Chiara Falcomatà, Sebastian A. Widholz, Albulena Toska, Fabio Boniolo, Constantin Schmitt, Vanessa Gölling, Jonathan Swietlik, Jonas Mir, Moritz Jesinghaus, Felix Meissner, Roland Rad, Marc Schmidt-Supprian, Dieter Saur. Pancreatic cancer subtype-specific secreted factors determine the immunosuppressive tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2514.
Abstract 6372: Nanodrug delivery system for non-genotoxic p53 activator INZ-C
Authors: Nimisha Bhattarai, Jieqiong Wang, Daniel Nguyen, Xiaoxiao Yang, Linh Helmers, Jennifer Paruch, Li Li, Yiwei Zhang, Kun Meng, Alun Wang, Janarthanan Jayawickramarajah, Binghe Wang, Shelya Zeng, Hua Lu
Journal: Cancer Research (2022)

Abstract p53 is a known tumor suppressor protein whose gene is altered in 50% of all human cancers, while its function is inactivated in the many cancers harboring wild type p53, making it an attractive target for targeted cancer therapies. In this regard, our lab had previously discovered a small molecule, Inauhzin (INZ C), as a potent non-genotoxic p53 activator. In an effort to improve the bioavailability and efficacy, we have now encapsulated the INZ C small molecule in a chitosan/cyclodextrin nanoparticle delivery system. Evaluation of in vitro/in vivo activity and protien expression suggests nanoparticle encapsulation of INZ-C (n-INZ-C) improved p53 induction and inhibition of cell growth in lung and colorectal cancers, while maintaining a minimal effect for MEF and Wi38 normal cells. These results are consistent with the significantly reduced cellular uptake observed for normal cells as compared to the cancer cells. H/E staining of tissues for mice treated with n-INZ-C reveals no toxicity to other organs as well. Additionally, n-INZ-C demonstrates the ability to block migration of cells in vitro as demonstrated by both wound healing and trans-well migration assays. Our in vivo pharmacokinetic evaluation suggests nanoparticle encapsulation doubles the half-life of INZ-C from 2.5 to 5 h. These results suggest that nanoparticle encapsulation improved activity and bioavailability of INZ-C while maintaining the non-toxic nature of INZ-C in normal cells. In addition, we unveiled GRP78 as a potential new target of INZ-C and found out that knockdown of GRP78 can alleviate the inhibitory effect of INZ-C on lung and colorectal cancer proliferation. Further studies now focus on revealing the mechanism of enhanced cellular uptake for INZ-C in cancer cells as comapred to normal cells. Thus, these results demonstrate that we have established a nanoparticle system that could enhance the bioavailability and efficacy of INZ-C as a potential anti-cancer therapeutic and also identified a novel target of INZ-C. Citation Format: Nimisha Bhattarai, Jieqiong Wang, Daniel Nguyen, Xiaoxiao Yang, Linh Helmers, Jennifer Paruch, Li Li, Yiwei Zhang, Kun Meng, Alun Wang, Janarthanan Jayawickramarajah, Binghe Wang, Shelya Zeng, Hua Lu. Nanodrug delivery system for non-genotoxic p53 activator INZ-C [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6372.